期刊
INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY
卷 40, 期 11, 页码 2492-2507出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.biocel.2008.04.011
关键词
YB-1; cisplatin; chemoresistance; microarray; nuclease; splicing
资金
- Canadian Institutes of Health Research
- Cancer Research Society
YB-1 is a protein involved in DNA repair, transcription, splicing, translation, and confers cisplatin resistance in several cancers. However, it is unknown which YB-1 activity is required for this resistance. To identify the mechanism(s) by which nuclear YB-1 confers cisplatin resistance, we generated several YB-1 mutants and tested their impact on resistance in the mammary tumor cell lines MCF7 and MDA-MB-231. Transfection of wild type YB-1 bestowed cisplatin resistance in such cells but a mutant YB-1 with a point mutation at position 175 (YB-1((E175A))) did not. A truncated YB-1((1-205)) increased cisplatin resistance above the levels conferred by wild type YB-1. The truncated YB-1((1-205)) has intact nuclease activities but could not separate a DNA duplex containing a Y-box sequence (activities associated with DNA repair). Moreover, this truncated YB-1((1-205)) did not alter splicing of the adenovirus El A pre-mRNA minigene as it had low binding affinity for several splicing factors. In contrast, the mutant YB-1((E175A)) protein behaved like wild type YB-1 regarding all these activities but yet did not confer cisplatin resistance. Finally, transfection of mutant YB-1((E175A)) had low impact on overall transcription. The wild type and truncated YB-1((1-205)) induced important but different alterations in gene expression as revealed by microarray analyses. Our results indicate that the splicing and the nuclease activities associated with YB-1 have minor impact on cisplatin resistance. In contrast, the global expression profiles displayed by both wild type and truncated YB-1((1-205)) revealed several chemoresistance signatures which differed depending on the genetic status of the breast cancer cell line used. (C) 2008 Elsevier Ltd. All rights reserved.
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